Sarecycline: A Narrow-Spectrum Antibiotic

Abstract and Introduction

Abstract

Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile.

Introduction

To date, one of the first-line classes of oral antibiotic treatments for moderate-to-severe acne has been tetracycline-class antibiotics due to their anti-inflammatory effects, antimicrobial activity, bioavailability, and lipophilicity.^[1] The pathogenesis of acne vulgaris is multifaceted with key factors being abnormal follicular keratinization, Cutibacterium acnes (C. acnes) proliferation/colonization, and increased sebum production.^[2] Inflammation also ensues with the expression and upregulation of inflammatory factors/cells such as CD3+, CD4+ T cells, interleukin-1, integrins, toll-like receptors, and macrophages.^[2]

Various methods for grading acne severity have been debated. Consensus remains elusive, as acne assessment must account for a spectrum of factors such as the number, location, type of lesions, associated scarring, and psychosocial influences.^[1,3] In fact, the established scoring tools Global Acne Grading System (GAGS) and Investigator Global Assessment (IGA), which are widely used in clinical trials, FDA efficacy endpoints, and patient care, do not account for all the associated factors in acne assessment.^[3]

Moderate-to-severe acne classically presents with inflamed papules, pustules, and occasional nodules with lesions commonly affecting the face, chest, and back.^[4,5] Oral antibiotics are a mainstay of treatment (Table 1).^[1] Tetracyclines, specifically doxycycline and minocycline, are broad-spectrum antibiotics widely used for acne treatment as they limit inflammation by inhibition of protein synthesis and proliferation of C. acnes.^[6] However, because of their broad-spectrum activity, tetracyclines not only contribute to the emergence of bacterial resistance, but also disrupt the gut and skin normal microflora, resulting in dysbiosis.^[7,8] Dysbiosis of the gut has been linked to inflammatory bowel disease. Doxycycline has shown to be associated with 2.25-fold increase in the risk of developing Crohn's disease.^[9]

In 2018, a new tetracycline derivative, sarecycline, was US FDA-approved for the treatment of inflammatory lesions of non-nodular, moderate-to-severe acne vulgaris in patients aged 9 years and older.^[10] This once-daily 1.5 mg/kg antibiotic exhibits a better tolerability and efficacy profile as a result of its narrow-spectrum coverage against C. acnes and clinically-relevant gram-positive bacteria with little activity against gram-negative bacteria commonly found in the human gut.^[10] In vitro studies by Zhanel et al. showed that all tetracyclines had similar activity against C. acnes, even isolates highly resistant against erythromycin ranging at minimum inhibitory concentration (MIC) of 0.5 µg/mL to 32 µg/mL.^[6] Activity against methicillin-susceptible and resistant isolates of Staphylococcus aureus (including MRSA) revealed a MIC90 of all tetracyclines, including sarecycline, to be 0.5 µg/mL.^[6] Compared to doxycycline and minocycline, sarecycline had little or no activity against gram-negative enteric bacilli with MIC50 at 32 µg/mL (16-fold less than doxycycline and minocycline).^[6]

Table 1. Oral antibiotics available for moderate-to-severe acne treatment. ^1,24,25
Name	Mechanism of Action	Coverage	Safety Profile	Strength of Recommendation	Additional Comments
Sarecycline	Bacteriostatic; inhibits 30S ribosomal subunit of bacteria; extends to mRNA and increases inhibitory effect	Narrow-spectrum; clinically relevant gram-positive bacteria	• GI disturbance (<5%) • Vestibular effects (<1%) • Photosensitivity (<1%)\ • Vulvovaginal candidiasis (0.3–1.1%)	A	• Least likely to cause GI upset • Less likely to induce bacteria resistance
Minocycline	Bacteriostatic; inhibits 30S ribosomal subunit of bacteria	Broad-spectrum; gram-positive, gram-negative, and atypical bacteria	• GI disturbance (1.5–25%) • Vestibular toxicity (~10%) • CNS problems (~17%) • Vulvovaginal candidiasis • Blue/grey skin pigmentation • Rare but serious autoimmune disease	A	• Most lipophilic among tetracyclines • Can cause minocycline-related autoimmune disorders
Doxycycline	Bacteriostatic; inhibits 30S ribosomal subunit of bacteria	Broad-spectrum; gram-positive, gram-negative, and atypical bacteria	• GI disturbance (10–25%) • Photosensitivity (15–30.5%) • Vulvovaginal candidiasis	A	• Most likely to cause photosensitivity and GI problems when compared to the rest of the tetracyclines
Tetracycline	Bacteriostatic; inhibits 30S ribosomal subunit of bacteria	Broad-spectrum; gram-positive, gram-negative, and atypical bacteria	• GI disturbance • Vulvovaginal candidiasis • Fixed drug eruptions • Dizziness • Tooth discoloration	A	• Must be taken on an empty stomach
TMP-SMX	Bactericidal due to synergy; TMP: folic acid analog that inhibits the enzyme dihydrofolate reductase SMX: blocks bacterial synthesis of folic acid	Gram-positive, and gram-negative bacteria, fungi, protozoa	• Hyperkalemia • Renal insufficiency • Stevens-Johnson syndrome/toxic epidermal necrolysis	B	• Adverse effects are mostly due to sulfonamides
TMP	Bacteriostatic; folic acid analog that inhibits the enzyme dihydrofolate reductase	Gram-positive, and gram-negative bacteria, fungi, protozoa	• Drug eruption	B
Erythromycin	Bacteriostatic; inhibits 50S ribosomal subunit of bacteria	Anaerobic and aerobic grampositive cocci	• GI disturbance • QT prolongation	A	• High resistance rate
Azithromycin	Bacteriostatic; inhibits 50S ribosomal subunit of bacteria	Anaerobic and aerobic grampositive cocci	• GI disturbance	A	• Dosed intermittently due to long half-life

Table 1. Oral antibiotics available for moderate-to-severe acne treatment. ^1,24,25

Name

Mechanism of Action

Coverage

Safety Profile

Strength of Recommendation

Additional Comments

Sarecycline

Bacteriostatic; inhibits 30S ribosomal subunit of bacteria; extends to mRNA and increases inhibitory effect

Narrow-spectrum; clinically relevant gram-positive bacteria

• GI disturbance (<5%)
• Vestibular effects (<1%)
• Photosensitivity (<1%)\
• Vulvovaginal candidiasis (0.3–1.1%)

• Least likely to cause GI upset
• Less likely to induce bacteria resistance

Minocycline

Bacteriostatic; inhibits 30S ribosomal subunit of bacteria

Broad-spectrum; gram-positive, gram-negative, and atypical bacteria

• GI disturbance (1.5–25%)
• Vestibular toxicity (~10%)
• CNS problems (~17%)
• Vulvovaginal candidiasis
• Blue/grey skin pigmentation
• Rare but serious autoimmune disease

• Most lipophilic among tetracyclines
• Can cause minocycline-related autoimmune disorders

Doxycycline

Bacteriostatic; inhibits 30S ribosomal subunit of bacteria

Broad-spectrum; gram-positive, gram-negative, and atypical bacteria

• GI disturbance (10–25%)
• Photosensitivity (15–30.5%)
• Vulvovaginal candidiasis

• Most likely to cause photosensitivity and GI problems when compared to the rest of the tetracyclines

Tetracycline

Bacteriostatic; inhibits 30S ribosomal subunit of bacteria

Broad-spectrum; gram-positive, gram-negative, and atypical bacteria

• GI disturbance
• Vulvovaginal candidiasis
• Fixed drug eruptions
• Dizziness
• Tooth discoloration

• Must be taken on an empty stomach

TMP-SMX